Vasodilator reactivity is attenuated in normotensive blacks and this may contribute to their enhanced susceptibility to hypertension and its complications. However, the mechanisms responsible for this phenomenon are unknown. We therefore studied nitric oxide (NO)-dependent and -independent vasorelaxation in healthy blacks and whites to investigate the nature of racial differences in vasodilator function. Forearm flow responses to intraarterial infusion of increasing doses of acetylcholine (a vasodilator that stimulates endothelial release of NO), sodium nitroprusside (an exogenous NO donor), and isoproterenol (a -adrenergic agonist whose vasodilator effect stems from the combination of direct smooth muscle stimulation and endothelial NO release) were studied in 18 normotensive whites and 18 blacks using strain-gauge plethysmography. A blunted vasodilator response to acetylcholine (7.2+/-1.1 vs 14.4+/-1.8 mL/min/dL; P<0.001) and sodium nitroprusside (8.2+/-1.1 vs 12.1+/-1.3 mL/min/dL; P<0.001) was observed in blacks compared to whites, suggesting decreased cyclic GMP-mediated smooth muscle relaxation. The vasodilator effect of isoproterenol was lower in blacks than in whites both before (10.9+/-1.7 vs 14.9+/-1.5 mL/min/dL; P=0.006) and after L-NMMA (6.1+/-1.2 vs 10.1+/-0.8 mL/min/dL; P<0.001), implying that cyclic AMP-dependent vasodilator response to isoproterenol is diminished in blacks. No significant difference was observed in the hyperemic response to forearm ischemia. Compared to whites, healthy blacks have reduced vasodilation in response to NO-dependent and -independent stimuli. This difference seems related to an attenuation in cyclic nucleotide-mediated vascular smooth muscle relaxation and may play a role in the increased prevalence of hypertension and its complications in blacks.